The use of hydromorphone as first-line therapy for acute migraine in the emergency setting is being questioned following results of a randomized trial that show prochlorperazine, a dopamine receptor antagonist, is overwhelmingly superior.
The study of patients presenting to the emergency department (ED) showed that twice as many of those who received a single dose of intravenous (IV) prochlorperazine achieved headache relief within 2 hours compared with those who received a single dose of IV hydromorphone.
“The use of hydromorphone as a first-line therapy for acute migraine is probably inappropriate,” lead author, Benjamin W. Friedman, professor, emergency medicine, Albert Einstein College of Medicine, New York City, told Medscape Medical News.
Dr Friedman said he did not expect prochlorperazine to perform as well as it did against hydromorphone. Rather, he was expecting “downstream” differences between the two drugs in terms of return visits to the ED and worsening of the underlying migraine disorder.
In fact, prochlorperazine performed so well the study was stopped early.
The findings were published online October 18 in Neurology.
Sustained Relief
Parenteral opioids are used to treat migraine in more than 50% of all ED visits. Hydromorphone is the most common opioid used and is administered in 25% of all migraine visits.
Dr Friedman suspects opioids are commonly used because they are easy to use, effective, and well tolerated in this setting. In addition, clinicians are “familiar” with these drugs and prescribe them for “a variety of aches and pains” in the ED, he said.
However, a recent guideline from the American Headache Society (AHS) notes that little high-quality evidence supports the use of these drugs for acute migraine.
To examine the efficacy of hydromorphone as first-line treatment for acute migraine, the investigators conducted a randomized, double-blind ED-based study.
Participants included 127 patients with acute migraine presenting to one of two EDs in New York City. Inclusion criteria were no opioid use in the previous month and no history of opioid addiction.
Patients were randomly assigned to receive 10 mg IV prochlorperazine plus 25 mg diphenhydramine (to prevent akathisia) or to 1 mg IV hydromorphone plus saline placebo.
Assessors used a scale on which patients described their headache as severe, moderate, mild, or none. They used this scale every hour in the ED until the patient was discharged or 4 hours had elapsed.
To assess functional impairment, they used another four-item scale that assessed patients as severely impaired, moderately impaired, mildly impaired, or not impaired.
The primary outcome in the study was sustained headache relief, defined as a reduction in headache level to mild or none within 2 hours of receiving medication, not requiring rescue analgesics, and not relapsing to worse than mild for 48 hours.
The study was halted after 127 patients had been enrolled because of overwhelming superiority of prochlorperazine.
In this group, 60% of the participants achieved the primary outcome compared with 31% in the hydromorphone group (difference, 28 percentage points [95% confidence interval (CI), 12 – 45 percentage points]; number needed to treat [NNT], 4 [95% CI, 2 – 9]).
A secondary analysis allowed for an additional dose of the same medication, if requested. Sustained headache relief after one or two doses of medication was achieved by 60% of the prochlorperazine group and 41% of the hydromorphone group (difference, 19 percentage points [95% CI, 2 – 36 percentage points]; NNT, 6 [95% CI, 3 – 52]).
Practice Changing
The prochlorperazine group had less functional impairment at 1 hour (none had severe impairment compared with 9% in the hydromorphone group), required fewer second doses (8% vs 31%), required fewer rescue medications (6% vs 36%), and stayed in the ED for a shorter period.
Fewer adverse events (AEs) occurred in the prochlorperazine group. In these patients, the most common AE was anxiety or restlessness, reported by about 5% of patients. In the hydromorphone group, the most common AE was dizziness or weakness, experienced by some 14% of patients.
At the 48-hour follow-up, patients were asked to rate restlessness and drowsiness as “a lot,” “a little,” or “none.” These two AEs were about equally distributed between the two groups.
At this time point, study participants were asked whether they would want the same medication during a subsequent ED visit. Almost three quarters (74%) of those in the prochlorperazine group and two thirds (68%) of the hydromorphone group indicated that they would.
For longer-term outcomes, researchers ascertained the number of headache days and return visits to the ED. They also used the Headache Impact Test (HIT), which rates the severity of the underlying migraine disorder, and the Migraine Disability Assessment Scale (MIDAS), which assesses the influence of headaches on daily life.
There were no between-group differences in the number of headache days, HIT score at 1 month, and MIDAS score at 3 months. There were also no differences in return visits to the ED.
Dr Friedman expected that the hydromorphone patients would report worse long-term outcomes because the prevailing thought has been that opioids worsen the underlying pain condition and result in more visits to the ED and additional exposure to opioids.
“I was surprised that all the difference that we saw was short term, that we didn’t see any long-term impact.”
The results suggest that addiction may not be an issue for those who receive an opioid in the ED.
“One or two doses of an IV opioid in the [ED] probably does not have an impact on what happens to patients subsequently,” said Dr Friedman.
Although the mechanism of action of antidopaminergic agents in migraine is not fully understood, dopamine is part of the nociceptive pathway, so the drug is likely somehow disrupting that pathway, said Dr Friedman.
When such agents were originally used as antinausea medications, researchers noticed that these drugs were unexpectedly curbing pain as well as nausea, he said.
Dr Friedman expects that with this new “high-quality evidence,” the next version of the AHS’s headache guideline “will have a much stronger recommendation against hydromorphone.”
He said he hopes the new study will change practice in EDs across the country, where “millions and millions of patients are getting hydromorphone.”
Confirmatory Findings
Commenting on the findings for Medscape Medical News, Kathleen Digre, MD, professor of neurology, director, Center of Excellence in Women’s Health, division director, headache and neuro-ophthalmology, University of Utah, Salt Lake City, and a fellow of the American Academy of Neurology, said the study was “very well designed.” The study groups were well matched and “typical” of those presenting to EDs across the United States, she noted.
The findings, said Dr Digre, who is president-elect of the AHS, confirm prior research showing the superiority of prochlorperazine compared with narcotics.
“The study provides further evidence of previously published evidence-based guidelines for IV antidomaminergic treatment of migraine in the [ED].”
Dr Digre also agreed that the results don’t support assertions that patients treated with hydromorphone have long-term sequelae, such as opioid addiction, recurrent trips to the ED for additional opioids, or more severe headaches.
She pointed out that because the study excluded patients taking opioids, “we can’t generalize to the population of patients who take opioids frequently.”
In addition, because the two study sites were in urban areas of New York City, the results “may not generalize to other areas completely.”
Another study limitation, said Dr Digre, was that the authors didn’t look at drugs that participants had been taking before the study, some of which could be linked to analgesic overuse, or collect data on preventive medications patients were receiving after their ED discharge.
“This would have been helpful information,” she said.
Dr Friedman and Dr Digre have disclosed no relevant financial relationships.
Neurology. Published online October 18, 2017. Abstract
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